The long-term goal of this project is to define the physiologic response of the ileocecal sphincter (ICS) to feeding and to determine the contribution of various components of the anatomic ICS to these physiologic responses. These studies will contribute towards an understanding of the integrative role, if any, of the ICS between ileal and colonic function. The project will consist of in vivo studies on the anesthetized cat in which intraluminal pressures and serosal myoelectric activity are recorded simultaneously and in vitro muscle strip studies which will also allow the simultaneous recording of extracellular electrical activity and contractile activity. Discrepancy exists between in vivo responses seen at the ICS to transmural stimulation and to intravenous neurohumoral agents and the in vitro response of ICS muscle strips to these same stimuli. Experiments will be designed to determine the reason for such discrepancy; to determine which specific parts of the anatomic ileo-cecal-colonic apparatus contributes to the physiologic and in vivo ICS responses; and to determine whether in vivo responses depend on an integrated response of the ileum, ICS and colon. The pathway and neurotransmitters mediating the ICS reflex responses to ileal and colonic balloon distension will be investigated using neurotoxin, myomectomy techniques and pharmacologic antagonists of classical neurotransmitters. In addition, the mediator of the stimulus relaxation in vitro to transmural electrical stimulation will be investigated. Those agents already demonstrated to induce ICS relaxation will be studied in addition to VIP, the major candidate for the neurotransmitter in non-cholinergic, non-adrenergic nerves. This will be examined by means of tachyphylaxis. Peptides which are putative neurotransmitters will be investigated in vivo an in vitro for their action at the ICS and for their possible role in mediating the gastro-ileocolonic response.